The sirtuins are highly conserved enzymes that are found in organisms ranging from bacteria to humans. In yeast, Sir2 was studied to slow aging by silencing transcription through histone deacetylation in an NAD+ dependent manner (Sauve et al., Annu. Rev. Biochem., 75: 435-436 (2006); Imai et al., Nature, 403: 795-800 (2000)). The mammalian ortholog NAD-dependent deacetylase, SIRT1, has numerous known substrates, including PGC1-a, NF-kB, p53, and FOXO1 (Brunet et al., Science, 303: 2011-2015 (2004); Rodgers et al., Nature, 434: 113-118 (2005); Yeung et al., EMBO J., 23: 2369-2380 (2004); Vaziri et al., Cell, 107: 149-159 (2001)). Many other NAD+ dependent protein deacetylases have been identified and found to regulate a variety of cellular processes such as DNA silencing, metabolic control, apoptosis, and cell cycling regulation (Guarente, Nature, 444: 868-874 (2006); Lin et al., Nature, 418: 344-348 (2002)).
Among the seven mammalian sirtuins (SIRT1 to −7), three sirtuins (SIRT3, 4 and 5) localize to mitochondria although less is known about the substrates in mitochondrial organelles (Onyango et al., Proc. Natl. Acad. Sci. USA, 99: 13653-13658 (2002); Haigis et al., Cell, 126: 941-954 (2006)). SIRT3 is known as a NAD+ dependent deacetylase involved in deacetylation of acetyl-CoA synthetase 2 and found to regulate global mitochondrial acetylation (Hallows et al., Proc. Natl. Acad. Sci. USA, 103: 10230-10235 (2006); Schwer et al., Proc. Natl. Acad. Sci. USA, 103: 10224-10229 (2006)). SIRT4 is a ADP-ribosyntransferase and regulates glutamate dehyderogenase (GDH) enzyme activity by transferring ADP-ribose to repress the activity of glutamate conversion to α-ketoglutarate (Sener et al., Nature, 288: 187-189 (1980)).
For SIRT5, its physiological substrates, functions, and the localization in mitochondria have been indecisive (Haigis et al., supra; Schlicker et al., J. Mol. Biol., 382: 790-801 (2008)). It was reported that SIRT5 is a NAD+ dependent deacetylase, localized in mitochondrial matrix (Schuetz et al., Cell, 15: 388-389 (2007)). Activation of SirT5 is known to deacetylate the mitochondrial enzyme carbomoyl phosphate synthetase 1 (CPS1). As mitochondria are key players in metabolism, energy maintenance, and apoptosis, disruption of mitochondrial pathways can lead to metabolic disease, oxidative damage, and cancer, and activation of those same pathways can treat or prevent metabolic disease, oxidative damage, and cancer. Activation of these pathways can also mimic caloric restriction and treatment for aging and prevention of senescence.